Tertiary-aminoalkyl x-substituted



Patented Feb. 16, 1954 2,669,565 TERTIARY-AMINOALKYL 4-SUBSTITUTED- AMINO-Z-ALKOXY THIOLBENZOATES AND THEIR PREPARATION Raymond 0. Clinton, North Stanley 0. Laskowski, to Sterling Drug Inc. poration of Delawar Greenbush, and

Menands, N. Y., assignors New York, N. Y., a core No Drawing. Application August 25, 1951, Serial No. 243,738

20 Claims. 1 This invention relates to tertiary-aminoalkyl 4-substituted-amino-2-alkoxythiolbenzoates and to their preparation.

The compounds have the general formula COS-X-NRR1 where X is a lower alkylene radical having from two to four carbon atoms, NRR1 is a tertiaryamino radical, R2 is a lower alkyl radical having from one to six carbon atoms and'Rs is a lower alkyl radical having from one to six carbon atoms, inclusive, or a lower hydroxyalkyl radical having from two to six carbon atoms. These esters have valuable pharmacological properties,

and in particular, local anesthetic activity.

In the above general formula, the lower alkylene radical designated as X has from two to four carbon atoms and has its two free valence bonds on diflerent carbon atoms. such examples as --CH2CH2-, CH2CH2CH2-,

diisopropylamino, ethyl-n-propylamino, di-nbutylamino, di-n-hexylamino, and the like. Further, the tertiary-amino radical designated as NRR1 encompasses saturated N-hetero-monocyclic radicals having from five to six ring atoms, illustrated by examples such as l-piperidyl; (lower a'lkylated)-1-piperidyl such as 2-methyll-piperidyl, B-ethyI-I-piperidyl, 4-methy1-1-piperidyl, 2,6-dimethyl-1-piperidyl; l-pyrrolidyl; (lower alkylated) -1-pyrrolidyl such as 2-methy1- l-pyrrolidyl, 2,5-dimethyl-1-pyrrolidyl; 4-morpholinyl; and the like. In the above formula, B: when a lower alkyl radical having from one to six carbon atoms includes radicals such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-amyl, 2- amyl, n-hexyl, and the like. R3 when representing a lower hydroxyalkyl radical having from two to six carbon atoms includes radicals such as Z-hydroxyethyl, Z-hydroxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, B-hydroxy- 2,2-dimethylpropyl, z-hydroxybutyl, 4-hydr'oxy- Thus, X includes 2 butyl, 3-hydroxyamyl, 5-hydroxyamyl, droxyhexyl, and the like.

The tertiary-aminoalkyl 4-substituted-aminoz-alkoxythiolbenzoates of our invention. can be prepared by various methods. The method preferred in practicing our invention comprises treating a tertiary-aminoalkyl 4-amino-2-alkoxythiolbenzoate with a reducing agent in the presence of an alkanal or a hydroxyalkanal. This procedure is adaptable for the preparation of our compounds where R3 is an alkyl or a hydroxya'lkyl radical having from three to six carbon atoms, inclusive, the reactants being an alkanal or a hydroxy-alkanal, respectively, each having from three to six carbon atoms. Illustrative of this method of preparation is the formation of Z-diethylaminoethyl 4-n-propylamino-' 2-n-butoxythiolbenzoate or Z-diethylaminoethyl 4 (3 hydroxypropyl) amino 2 n butoxythiolbenzoate by treating Z-diethylaminoethyl 4- amino-2-n-butoxythio1benzoate in the presence of propionaldehyde '(propanal) or beta-hydroxypropionaldehyde (3-hy-droxy-1-propanal), re-' spectively, with a chemical reducing agent, such as zinc dust and acetic acid, iron and acetic acid, or with hydrogen in the presence of a. sulfur-in-,

sensitive catalyst, e. g., molybdenum sulfide,'co-' balt sulfide.

The intermediate tertiary-aminoalkyl 4-amino- 2-alkoxythiolbenzoates, which are disclosed and claimed in our copending U. S. Patent application Serial No. 216,272, filed March 17, 1950, are

conveniently prepared from 4-nitro-2-alkoxybenzoyl halides as shown in the following series of reactions where X, NRR1 and R2 have the meanings given hereinabove.

Thus, instep I a -nitro-Z-alkoxybenzoyl halide (A) [preparation disclosed in our copending U. 8. Patent applications Serial Nos. 168,843 and 168,844, each filed June 1'7, 1950] is treated with a tertiary-aminoalkanethiol (B') to yield a tertiary-aminoalkyl i-nitro-2-alkoxythiolbenzoate (C), which, in step II, is reduced to produce the corresponding ,tertiary-aminoalkyl 4-amino-2- alkoxythiolbenzoate (D). A specific illustration of this series of reactions is the formation of 2. diethylaminoethyl 4-a1nino-2-n-butoxythiolben zoate by treating a 4-nitro-Z-n-butoxybenzoyl halide, preferably the chloride, with 2-diethylaminoethanethiol to form 2-diethylaminoethyl 4- nitro-Z-n-butoxythiolbenzoate and reducing the nitro group of said thiol ester to form the corresponding z-diethylaminoethyl 4-amino2-nbutoxythiolbenzoate.

Another style of synthesis of the thiol esters of our instant invention is the direct alkylation of a tertiary-aminoalkyl 4-amino-2-alkoxythiolbenzoate with alkylating agents such as methyl iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, 2-hydroxyethy1 bromide. 4-hydroxybutyl. chloride, and the like, in the presence of a hydrogen. halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc. Thus, such treatment of Z-diethylaminoethyl 4-amino-2-n-butoxythiolbenzoate with methyl iodide, ethyl bromide. or Z-hydroxyethyi bromide yields Z-diethylaminoethyl 4-methylamino-2-n-butoxythiolbenzoate, 2-diethylaminoethyl 4-ethylamino-2-n-butoxythiolbenzoate or Z-diethylaminoethyl 4-(2hy droxyethyhamino 2 n butoxythiolbenzoate, respectively.

The tertiary aminoalkyl d-substitutemamino- 2 all ozwthio1benzoates of our invention are therapeutically active whether employed in the. form of their free basesv or in the form of their salts with relatively non-toxic, organic or inorganic acids. In. practicing our invention we sometimes found it convenient to.- isolate our compounds in. the form of their hydrochlorides. However, other acid addition salts are within the scope of our invention, such addition. salts including the hydrobromides, sulfates, phosphates, citrates, sulfamates, tartrates, succinates, ace tates, benzoates, oleates, and. the like.

Specific embodiments of our invention are i1- lustrated by the following examples.

was prepared in quantitative yield by refluxing a mixture of 98.5 g. of 4-nitro-2-methoxybenzoic acid and 295 g. of thionyl chloride for two and one-half hours, evaporating in vacuo, adding 200 ml. of dry benzene and again evaporating in vacuo. To a cooled solution of 63.9 g. of i-nitro- Z-methoxybenzoyl chloride dissolved in 400 ml. of dry benzene was added slowly, with stirring, 39.5 g. of Z-diethylaminoethanethiol dissolved in ml. of dry benzene, and the resulting reaction mixture was heated to boiling, cooled and diluted with, dry benzene to a total volume of one liter. The tan colored product that separated on cooling was filtered and recrystallized, with decolorization using activated carbon, from absolute ethanol-petroleum ether, thereby yielding the desired product, 2-diethylaminoethyl 4-nitro-2- methoxythiolbenzoate in the form of its hydrochloride. After being dried at C. in vacuo, it melted at 146.4l.e7.9 C. (cor.).

, In the preparation of the acid chlorides where the 2-alkoxy substituent is higher in carbon content than ethoxy (e. g., 4-nitr02-n-butoxybenzoyl chloride), the reaction is preferably run in the presence of pyridine as a hydrogen chloride acceptor to minimize cleavage of the alkoxy group. This procedure is illustrated as follows: To 1 mole of acid, e. g., 4-nitro-2-n-butoxybenzoic acid, and 1.2 moles of pure pyridine in 4 volumes of dry benzene was added 1.0 mole of thionyl chloride at 25 C., the mixture refluxed for about twenty minutes, cooled in ice, treated with stirring with 1.0 mole of the tertiaryarninoalkanethiol, e. g., il-(l-piperidyllpropanethiol, and the reaction mixture mixed well. The solvent was removed in vacuo and the residue dissolved in water. Excess ammonium hydroxide was added and the mixture extracted with toluene. The toluene solution was dried and the solvent removed in vacuo. More toluene was added and again evaporated in vacuo (this procedure was to remove pyridine), thereby leaving the pure base, e. g., 3-(l-piperidyl)propyl 'l-nitro-2n-butoxythiolbenzoate.

Additional tertiary -aminoalkyl d -nitro-2- alkoxybenzoates, in the form of their hydrochlorides, prepared according to the above described procedures from the appropriate 4-nitro-2- EX 1 alkoxybenzoyl chloride and tertiary are-inoalkanethiol are iven in Table I. (a). Tertzarwammoalkyl 4-mtro-Z allcoscythzol- 50 g benzoates TABLE 1 N02 These substances were prepared by reacting a 4enltro-2-alkoxybenzoyl halide, preferably the chloride, with a tertiary-aminoalkanethiol, as illustrated by: the following preparation of 55 on, z-diethylaminoethyl 4 nitrd- 2 methoxythiol- I benzoate: 4-Nitro-2-methoxybenzoyl chloride C0S-XNRR1 Hydrochloride, I l X M. r./ o. (COL) on; CHaCHzCH: I I-piperidyl 200.0-2Ol.l' CH3 CHzCHaCHz N(C2H5)e DIG-155.0 0H3 CHZCHZCHZGHZ. M02115): loan-110s CHzCHa C'HzCHzCHr N(C2H5;i! UTE-118.8 l CHzCHrCHs CHzCHz N(C:Hs2. l.(ll35.8 CHzCHnCHa CHzCHz. l-piperidal 18533-4873 CHzCHaCHa CHzCHzCH: l-piperldyl 196.6l08.0 l ottoman; GHZGHZ: 2'-GH;,-l-pipei'li1yl mac-21m omomomon; OHZCHJ N(G2H5)2 171.741 CHzOHzCHzCH: CH'zCH: l-piperidyl 1T9;3-lfl0.5 CHaCHaCHzCHa GHzC-HzCHz l.-piperidyl l7U.U-l7l.U g CHzCHzCHzCHz CHzCHz 2-GHs-l-pipcridyl lG5.0-l65.9 cmomoam omom M01133 NBA-194.6 1 CHgCHzCHzCHzCHzCH; CHcCHz' N(CzH5)z 1 l15.4-1l6.6 t

1 Thlolester base melts at 60.1-61.2? (1. (cm-g. "-Thiol ester base melts at 655457.7" C. (cor. Thlol esterbase melts at 55.3-57:2-C. (con).

Additional tertiary aminoalkyl 4 nitro-2- alkoxythiolbenzoates which can be prepared according to the foregoing procedure using the appropriate 4-nitro-2-alkoxybenzoyl chloride and tertiary-an1inoalkanethiol include the following: Z-diethylaminoethyl 4-nitro-2-ethoxythiolbenzoate; 3-(1-pyrrolidyl) propyl 4-nitro-2- n-propoxythiolbenzoate; 2 (2,5 dimethyl l pyrrolidyl) -ethyl 4 nitro 2 n hexoxythiolbenzoate; 4-dimethylaminobutyl 4-nitro-2-nbutoxythiolbenzoate; 2- di-n-butylamino) ethyl 4-nitro-2-isoamoxythiolbenzoate; 2- (3 -ethyll piperidyl) ethyl 4 nitro 2 isobutoxythiolbenzoate; 3-(Z-methyl-l-pyrrolidyl) propyl 4-nitro- 2- (3-amoxy) thiolbenoate; 3-dirnethylamino-2- propyl 4-nitro--2-n-butoxythiolbenzoate; 2-(4- morpholinyl) ethyl 4-nitro-Z-n-amoxythiolbenzoate; 2-(2-methyl-l-piperidyl) ethyl 4-nitro-2- ethoxythiolbenzoate; and 3-diethylaminopropyl 4-nitro-2-n-hexoxythiolbenzoate.

(b) Z-dz'ethylaminoethyl 4-amino-2-methomythiolbenzoate To a hot stirred mixture of 75.0 g. of powdered iron (ferrum reductum), 1 ml. of concentrated hydrochloric acid and 600 ml. of 50% ethanol was added slowly 78.0 g. of Z-diethylaminoethyl 4-nitro-2methoxythiolbenzoate hydrochloride over a period of about ten minutes. The resultant solution was heated with Stirring for another twenty minutes, after which time an excess (about g.) of sodium bicarbonate was added. The mixture was warmed and stirred for an additional twenty minutes, filtered through: a

filter aid and the insoluble material was washed well with hot absolute ethanol. The combined filtrates and washings were concentrated by distilling in vacuo, and the residue was cooled and extracted with ethyl acetate. The combined. ex

tracts were dried over anhydrous potassium car- J (con).

Anal.Calcd. for C14H22N202S1 N, 9.92. Found: N, 9.75.

The phosphate salt of this thiol ester was prepared by treating a solution of z-diethylaminoethyl 4-amino-Z-methoxythiolbenzoate in free base form in a suitable solvent, such as ethyl acetate, an equivalent amount of 85% phos-' phoric acid, filtering the precipitated phosphate and recrystallizing the same from dilute ethanol. The resultant salt, Z-diethylaminoethyl 4-amino- 2-methoxythiolbenzoate phosphate, melted at 188.2l90 C. (con) when dried at 100 C. in vacuo.

AnaZ.-Calcd. for C14H22N2O2S-H3PO4Z S, 8.42; N, 7.36; C, 44.19; H, 6.58. Found: S, 8.60; N, 7.35; C, 44.19; H, 6.44.

The dihydrochloride addition salt of this thiol ester can be prepared by dissolving a portion of said ester in free base form in a suitable solvent, such as ethyl acetate, and treating the solution with an excess of anhydrous ether containing 20% by weight of anhydrous hydrogen chloride. The gummy precipitate is separated from the supernatant liquid by decanting and is triturated with ethyl acetate. Again the ethyl acetate is decanted and the crude precipitate is recrystallized from absolute ethanol, absolute ethanolether or absolute ethanol-ethyl acetate and'dried; at C in vacuo. Thus obtained is 2-diethylaminoethyl 4-amino-2-methoxythiolbenzoate dihydrochloride.

The monohydrochloride salt of this thiol ester is prepared by dissolving the ester in free base form in a suitable solvent, such as ethyl acetate, treating the solution with an excess of anhydrous ether containing 20% by weight of anhydrous hydrogen chloride, triturating the gummy precipitate with ethyl acetate, as above, and dissolving the resulting crude dihydrochloride in a minimum quantity of hot absolute ethanol and to the solution is added a slight excess of the purl fied ester in free base form dissolved in a minimum quantity of hot absolute ethanol. The crystalline precipitate which separates on cooling is collected and washed with ethyl acetate. To ensure more complete precipitation, ethyl acetate can be added to the cooled mixture before filtering. Recrystallization of the precipitate from absolute ethanol or absolute ethanol-ethyl acetate yields, in purified form, Z-diethylaminoethyl 4-amino-2-methoxythiolbenzoate monohydrochloride.

Other tertiary-aminoalkyl 4-amino-2-alkoxy thiolbenzoates can be prepared according to the foregoing procedure using the corresponding tertiary-aminoalkyl 4-nitro-2-alkoxythiolbenzoate hydrochloride in place of 2-diethylaminoethyl 4-nitro-Z-methoxythiolbenzoate hydrochloride. Thus, Z-diethylaminoethyl 4-amino-2-ethoxythiolbenzoate, 3-(1-pyrrolidyl) propyl 4-amino-2-npropoxythiolbenzoate, 2-(2,5-dimethyl-l-pyrrolidyl) ethyl 4-amino-2-n-hexoxythiolbenzoate, 4- dimethylaminobutyl 4-amino-2-n-butoxythiol benzoate, Z-(di-n-butylamino) ethyl 4-amino-2- isoamoxythiolbenzoate, 2- (3-ethyl-1-piperidyl) ethyl 4-amino-2-isobutoxythiolbenzoate, 3-(2- methyl-l-pyrrolidyl) -propyl 4-amino-2- (3- amoxy) thiolbenzoate, 3-dimethylamino-2-propyl 4-amino-2-n-butoxythiolbenzoate, 2- 4-morpholinyDethyl 4-amino-amino-2-n-amoxythiol benzoate, 2-(2-methyl-l-piperidyl) ethyl 4-amino-2-ethoxythiolbenzoate and 3-diethylaminopropyl 4-amino-2-n-hexoxythiolbenzoate are ob; tained, respectively, from the hydrochlorides of 2-diethylaminoethyl 4-nitro-2-ethoxy-thiolbenzoate, 3-( l-pyrrolidyl) propyl 4-nitro-2-n-propoxythiolbenzoate, 2- (2,5-dimethyl-l-pyrrolidyl) ethyl 4-nitro 2- n hexoxythiolbenzoate, 4-dimethylaminobutyl 4-nitro-2-n-butoxythiol' benzoate, 2- (di-n-butylamino) ethyl 4-nitro-2- isoamoxythiolbenzoate, 2- (3-ethyl-1-piperidyl) ethyl 4-nitro-2-isobutoxy-thiolbenzoate, 3-(2- methyl-l-pyrrolidyl)propyl 4 nitro 2 (3- amoxy)-thiolbenzoate, 3-dimethylamino-2-propyl 4-nitro-Z-n-butoxythiolbenzoate, 2-(4-morpholinyl) ethyl 4-nitro-2-n-amoxythiolbenzoate, 2- Z-methyl-l-piperidyl) ethyl 4-nitro-2-ethoxythiolbenzoate and B-diethylaminopropyl 4-nitro- 2-n-hexoxythiolbenzcate. Alternatively, the foregoing reactions can be run using said tertiaryaminoalkyl 4-nitro-2-all oxythiolbenzoates in form of their free bases.

(0) Z-diethylaminoethyl ei-n-amylamino-Z- methorythz'olbenzoate 7 utes: "The resulting mixture was refluxed with stirrins forone hour. Another 1 ml. portion. of n.-valeraldehyde was added and refluxing" continued for another thirty minutes. The hot reaction mixture was filtered, and the filtrate was cooled; and made basic to litmus with concentrated ammonium hydroxide. The product. that separated, was extracted with benzene. During this particular extraction it was necessary to filter the extraction. mixture through, a filter-aid in order to break up an emulsion. The benzene extract was then dried over anhydrous potassium carbonate. Removal of the benzene in vacuo yielded, as a viscous, golden brown oil, an exce1- lent yield of Z-diethylaminoethyl 4-n-amylamino-2-methoxythiolbenzoate.

This product was converted into its hydrochloride addition salt as follows: The. basic. ester was dissolved in ethyl acetate and the resultingv solution was treatedchloride (20% by weight of HCl) with cooling, whereupon the dihydrochloride separated. as a gummy material. The supernatant liquid was decanted and the gum. was dissolved in. a minimum quantity of hot absolute ethanol, 1-2 ml. of etheral-hydrogen chloride was added, the resulting solution cooled and ethyl acetate was added to turbidity. The resulting white crystalline product, Z-diethylaminoethyl 4-n-amylamino-2- methoxythiolbenzoate dihydrochloride, melted at.l.49.2150.5C. (con). whenrecrystallized twice from absolute ethanol-ethyl acetate, containing l2 ml. of ethereal-hydrogen chloride.

Anal..--Calcd. for C19Ha2N20zS-2-HC1? C, 53.89;

H, 8.09; S, 7.57. Found: C, 53.82; H.189; S, 7.44.

Following the above procedure but using n-caproaldehyde (.l-hexanal). in place of n-valeraldehyde there is obtained Z-diethylaminoethyl 4-n-hexylamino2methoxythiolbenzoate.

other tertiary-aminoalkyl 4-n-amylamino -2- alkoxythiolbenzoates which can be prepared. according to the foregoing procedure using the appropriate tertiary-aminoalkyl 4-amino-2-alkoxythiolbenzoate in place of 2-diethylaminoethyl 4. arnino-'2-methoxythiolbenzoate include the following: 2-diethylaminoethyl 4'n-amylamino2- ethoxythiolbenzoate; 3-(1 pyrrolidyl) propyl d-n-amylamino-Z-n-propoxythiolbenzoate; 4-dimethylaminobutyl Q-n-amylamino-Z-n-butoxythiolbenzoate; 2- ('di-n-butylaminolethyl 4-n- 3 and 2- I amylamino-2:-isoamy1oxythiolbenzoate; (2-methyl-1-piperidyl)ethyl- 4-n-amylamino-2- ethoxythiolbenzoate.

EXAMPLE 2 v (a) 3-cliethylamin0propyl 4-amz'n0-2-methoxythz'olbenzoate on s-dieth zammo mp z 4-n-butylamino- 2- methoxythzolbenzoate To a warm. stirred. mixture of 12.5 g. of 3-dithylaminopropyl. i-amino-2-niethoxythiolbenre -alma. of zinc dust. 10.3 g. of glacial acetic with ethereal-hydrogen methoxythiolbenzoate,

acid and 200 ml. or ry ben ene. was added, 3.267v g. of I'i-rbllilYI'dldGhYde (.L-lmtanal) in 5.0. ml. of dr! benzene over a. period. of about fifteen minutes. The resulting mixture; was refluxed with stirring for one hour. Another 1 ml. portion of n-butyraldehyde was added andrefluxing continued for an additional thirty minutes. The hot reaction mixture was filtered; the filtrate was cooled and made basic to litmus with concentrated, ammo.- nium hydroxide. The oil that separated was taken up with dry benzene. The benzene extract was dr dv ov r anhydrous potassium carbonate. The benzene. was then removed by distilling in vacuo to yield. 13. g.. of 3,-diethylaminopropyl 4- n-butylamino-2-methoxythio1benzoate, an. amber, viscous oil.

This basic ester was purified by converting, it to its dihydrochloride acid addition salt and reacherating the. basic ester therefrom as. follows The basic ester was dissolved in ethyl acetate. The resulting solution. was washed well, with water. treated with ethereal-hydrogen chloride and cooled. The acid addition salt was extracted with water and the aqueous extract. was washed with ether, decclori'zed with decolorizing charcoal, and made basic to' litmus with concentrated ammonium hydroxide. The liberated base was taken up with ethyl acetate and the ethyl acetate solution was dried over anhydrous potassium carbonate. The ethyl acetate was removed by: distilling in vacuo and the resultant oil wa dissolved in aid-- solute ether. After the ethereal solution had been charcoaled, the ether was evaporated in vacuo, thereby yielding the product as an amber; viscous oil which was then dried at 0.03 mm. pressure of Hg for four hours;

Anal.--Calcd. for C19H32N2O2S: S, 9.09; N, 7.94. Found: S, 8.9-1; N, 7.70.

Alternatively, the above compound can be prepared by direct alkylation of 3-diethylaminopropyl 4amino-2-methoxythiolbenzoate with nbutyl bromide. Similarly, using methyl iodide, ethyl chloride or Z-hydroxyethyl bromide in place of n-butyl bromide, there is obtained, respectively, 3 diethylaminopropyl 4 methylamino 2 3-diethylaminopropyl-4- ethylamino 2 methoxythiolbenzoate or 3 diethylaminopropyl 4- (2-hydroxyethyl) amino-2- methoxythiolbenzoate.

Other tertiary-aminoalkyl l-n-butylamino-Z- alkoxythiolbenzoates which can be prepared according to the foregoing procedure using the appropriate tertiary-aminoalkyl 2-alkoxythiolbenzoat in place of 3-diethylaminopropyl -aminm 2-methoxythiolbenzoate include the following: 2- (2,5 dimethyl l pyrrolidyDethyl 4 n butylamino 2 n hexoxythiolbenzoate; 2 (3- ethyl l piperidyDethyl 4 n butylamino 2 isobutoxythiolbenzoate; 3 (2 methyl 1 pyrrolidyDpropyl 4 n butylarnino 2 -(3 amoxy)thiolbenzoate; 3 -'dimethylamino 2 propyl 4 n butylamino 2 n butoxythiolbenzoate; 2 (4 morpholinyl) ethyl 4 n 1 butylamino 2 n amoxythiolbenzoate; and 3 diethylaminopropyl 4 n butylamino 2 n hexoxythiolbenzoate.

EXAMPLE 3 (a) 3- (1 -piperz'dyl) propyl 4-cmino-2-methozythz'olbeneoate This preparation was carried out. according to the procedure described above for Example 11) using the following' reactants: 19.7 g, of powdered iron. 1 ml. or concentrated hydrochloric acid, e00 m1. of 50% ethanol and, 22.0 g. of 3-(1-piper idyDprop'yl 4-nitro-2-methoxythiolbenzoate hy drochloride. There was thus obtained a quantitative yield of 3-(1-piperidyl) propyl 4-amino-2- methoxythiolbenzoate, which in the form of its phosphoric acid addition salt melted at 202.5-203.4 C. (c012).

.Anal.Calcd. f! C1sI-I24N2O2S'H3PO'4: S, 7.88, H3PO4, 24.12. Found: S, 7.94; H3PO4, 24.20.

EXAMPLE 4 (a) v4 diethylamz'nobutyl 4 amino 2 methoxythiolbcnzoate When the procedure described above for Example lb was followed but using 37.8 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 490 ml. of 50% ethanol and 42.5 g. of 4-diethylarninobutyl 4-nitro-2-methoXy-thiolbenzoate hydrochloride, there was obtained 31 g. of 4- diethylaminobutyl 4-amino-Z-methoxythiolbenzoate. This thiol ester, in the form of its phosphoricacid addition salt, melted at 198.1-1991" C. (cor.).

AnaL-Calcd. for C1sH24N2O2S-H3PO4: S, 7.85, H3PO4, 24.00. Found: s, 7.85; HsPO4, 24.29.

(b) 4 diethylamz'nobutyl 4 n buty lamzno 2 methomythioilbenzoate When the procedure described above for EX- ample 2b was followed using 21 g. of 4-diethylaminobutyl 4 amino 2 methoxythiolbenzoate, 17.7 g. of zinc dust, 16.7 g, of glacial acetic acid, 300 ml. of dry benzene and'5.9 g. of n-butyraldehyde in 50 ml. of dry benzene, there was obtained 4 diethylaminobutyl 4 n butylamino- Z-methoxythiolbenzoate, an amber colored oil.

Anal.-'-Calcd. for C20H34N202S: N, 7.64; S, 8.74. Found: N, 7.49; S, 8.56.

EXAMPLE 5 (a) Z-diethylaminoethyl 4 amino-Z-n-butomythiolbenzoate (b) 2-diethylaminoethyl 4 n butylamz'no-Z-nbutorythzolbenzoate When the procedure described above for Example 2b is followed but using 2-diethy1amino- There was thus.

Ill

10 ethyl 4-amino-2-n-butoxythiolbenzoate in place of 3 diethylaminopropyl 4 amino-2-methoxythiolbenzoate the resulting product is 2-diethylaminoethyl 4-n-butylamino-2-n-butoxythiolbenzoate.

EXAMPLE 6 (a) Z-diethylaminoethyl 4-amz'no-2-n-propozcythiolbenzoate 'When the procedure described above for Example lb was followed but using 62.5 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 500 ml. of 50% ethanol and 64.0 g. of 2-diethylaminoethyl 4-nitro-2-n-propoxythiolbenzoate, there are obtained 40.0 g. of Z-diethylaminoethyl 4-amino-2-n-propoxythiolbenzoate. This thiol ester, in the form of its phosphate salt, melted at 1504-1513 C. (con).

AnaZ.-Calcd. for C1sH20IT202S-H3PO4: N, 6.85; H3PO4, 24.00. Found: 6.72; H3PO4, 23.98.

(b) 2 diethylamz'noethyl 4 n bun/lamina 2-1z-proporythzolbenzoates To a warm stirred mixture of 16.0 g. of 2-dia ethylaminoethyl 4-amino-2-n-propoxythiolbenzoate, 13.5 g. of zinc dust, 12.7 g. of glacial acetic acid and 200 ml. of dry benzene was added 4.5 g. of n-butyraldehyde in 50 ml. of dry benzene over a period of fifteen minutes. The resulting mixture was refluxed with stirring for one hour. Another 1 ml. portion of n-butyraldehyde was added and refluxing continued for an additional thirty minutes. The hot reaction mixture was filtered, and the filtrate was cooled and made basic to litmus with concentrated ammonium hydroxide. The product that separated was extracted with benzene (or ethyl acetate). The benzene extract was washed with water and dried over anhydrous calcium sulfate. Concentration of the dried benzene solution in vacuo yielded, as an amber, viscous oil, the theoretical amount of 2 diethylaminoethyl 4-n-butylamino-2-n-propoxythiolbenzoate.

This basic ester was converted into its dihydrochloride as follows: 5 g. of the ester was dissolved in ethyl acetate and to this solution was added an excess of ethereal-hydrogen chloride solution (20% by weight of HCl) whereupon the dihydrochloride separated as a gummy material. The mixture was diluted with absolute ether (to a total volume of about 500 ml.) and the supernatant liquid was decanted from the gummy precipitate. The precipitate was triturated three times with warm ethyl acetate and was then dissolved in a minimum amount of hot absolute ethanol, and to the resulting solution was added about 1 m1. of said ethereal-hydrogen chloride solution. The resulting solution was decolorized with decolorizing charcoal, cooled and treated with another one ml. portion of ethereal-hydrogen chloride solution and a small amount of dry acetone, whereupon there separated, as a finely divided pale yellow material, 2-diethylaminoethyl 4-n-butylamino-2-n-propoxythiolbenzoate dihydrochloride, which when recrystallized another time from absolute ethanol-acetone (dry) melted at 142,2-143.9 C. (cor.).

AnaZ.--Calcd. for C20H34N202S'2HC1I Cl, 16.13;

s, 7.29. Found: 01, 16.08; S, 7.16.

EXAMPLE 7 (a) Z-(I-piperidyDethyl 4-amz'no-2-n-propomythiolbenzoate This thiol ester was prepared according to the procedure described above for Example 1b but using the following reactants: 26.5 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 350 ml. of 50% ethanol and 28.0 g. of 2-(1-piperidyl) ethyl 4 nitro 2 n-propoxythiolbenzoate. The yield of the 4-amino thiol ester was 24 g. This ester in the form of its monohydrochloride addition salt melted at 89.2190.9 C. (con).

Anal-Calm. for CuHzeNzOzS-HCl-z N, 7.80; CI, 9.87; S, 8.93. Found: N, 7.54; Cl, 9.72; S, 9.05.

(b) 2-(1 piperidybethyl 4-n-butylamino z-npropoxythiobenzoate Following the procedure described hereinab'ove for Example 21) but using 2-(1-piperidyl)ethyl 4-amino-2-n-propoxythiolbenzoate in place of 3- diethylaminopropyl 4-amino-Z-methoxythiolbenzoate there is obtained 2-(l-piperidyllethyl 4-hbutylamino-2-n-propoxythiolbenzoate.

EXAMPLE 8 (a) 3 diethylam'inopropyl 4 amino-z-ethozwthiolbenzoate When the procedure described above for Example 1b was followed but using 35.3 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 400 ml. of dilute ethanol and 35.8 g. of 3- diethylaminopropyl 4-nitro-2-ethoxythiolbenzoate, there was obtained 30.8 g. of 3-diethylaminopropyl 4-amino-Z-ethoxybenzoate. This thiol ester, in the form of its monohydrochloride salt, melted at 175.0-1763" C. (con).

.Amllr-calcd. for C1sH2eN2O2S'I-ICII N, 8.07; Cl, 10.22. Found: N, 7.83; Cl, 10.40.

(b) 3-diethylaminopropyl 4 n hemyZamino-Z- ethozcythiolbeneoate When the procedure described above for Example 2b is followed but using 3-diethylaminopropyl 4 amino 2 ethoxythiolbenzoate and caproaldehyde (l-hexanal) in place of 3-diethylaminopropyl 4 amino-2-methoxythiolbenzoate and n-butyraldehyde, respectively, the resulting product is 3 diethylaminopropyl 4 n hexylamino-2-ethoxythiolbenzoate.

EXAMPLE 9 (a) Z-(I-piperidyl) ethyl 4-amino-2 n lmtoazythiolbenzoate When the procedure described above for Example 1b wasiollowed but using 27.1 g. of powdered iron, 1 m1. of concentrated hydrochloric acid, 350 ml. of dilute ethanol and 29.5 g. of 2-; piperidyl) ethyl 4-nitro-2-n-butoxythiolbenzoate, there was obtained about 27 g. of 2-(l-piperidyD ethyl 4 amino-2-n-butoxythiolbenzoate. This thiol ester, in the form of its monohydrochlor-ide salt, melted-at 172.3-173.9 C. (coin).

AnaZ.-Calcd. for CraHasNzOzS-HCI: N, 7.51; Cl, 9.50. Found: N, 7.38; Cl, 9.38.

(b) 2-(1 -piperidyl) ethyl 4 -n butylami'no-Z-nbutorythiolbenzoate When the procedure described above for Example 2b is followed but substituting -2-(1-piperidyDethyl 4-amino-2-n-butoxythiolbenzoate for 3-diethylaminopropyl 4-amino-2-meth'oxythiolbenzoate, the resulting ester is -2-(l-piperidyl) ethyl 4 nbutylamino-2-n-butoxythiolbenzoate.

EXAIVIPLE 10 (a) Z-(Z-methyl-I-piperidyl)ethyl 4-amino-2- n-butozythiolbenzoate This preparation was carried out according to the procedure described above for Example 1b but using 31.4 g. of .powdered iron, 1 ml. of con-- centrated hydrochloric acid, 400 ml. of dilute ethanol and 35.6 g. of 2-(2-methyl-l-piperidyhethyl 4 nitro -"2 n butoxythiolbenzoate. The product thus obtained was 2-'(2-"methyl-lpiperidyl) ethyl 4-amino-2-n-butoxythiolbenz0- ate (30 g.) which in the form or its hydrochloride salt melted at 191.2-192;3 C. (coin).

AnaZ.-Calcd. for CroHsoNzOzS-HCI: N, 7.24; Cl, 9.16. Found: N, 728; Cl, 9.02.

(b) 2- (Z-methyZ-I -piperidyl) ethyl 4-n-but1llamino-2-n-butoa:ythiolbenzoate When the procedure described above for E:- ample 2b is followed but using 2-"(2-me'thyl-l piperidyl) ethyl 4-amino-2-n-butoxythiolbenzoate instead of 3-diethylaminopropyl lemme-f2- m'ethoxythiolbenzoa'te, there is obtained 2-(2- methyl 1 piperidyl) ethyl 4-n-butylamino-"2-m butoxythiolbenzoate.

(a) Z-(Z-methyl-I-piperidyl)ethyl 4-amino-2- n-propomythiolbenzoate (5) Z-(Z-methyZ-I -piperidyl) ethyl 4-n-butylamino-2-n-propomythiolbenzoate Following the procedure described above for Example 2b but using 2-(2-methyl-l-piperidyl) ethyl 4-amino-2-n-propoxythiolbenzoate instead of 3-diethylaminopi opyl 4-amino-2-methoxythiolbenzoate, there is obtained 2-(2-methyl-lpiperidyl) ethyl 4 n butylam'ino-2-n-pr'opoxythiolbenzoate.

1 2 (a) 3-(1-piperidyhpmpyl 4-ammo-2-n-propoxythiolbenzoate When the procedure described above for Example 1b was followed but using 22.0 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 400 ml. of dilute ethanol and 24.0 g. of 3- (1 piperidyl) p'ropyl 4-nitro-2-n propoxythiolbenzoate, there was obtained about 22 'g. of '3-(l"- piperidyl) propyl 4- mino-2-n propoxythiolb'enzoate. This thiol ester. in the form or its dihydrochloride salt, melted at 170.4172.0 C. (con) with decomposition.

Anal-Caled. for CmI-Ir'a'NzO2S-2HCI: N, 0.84: S, 7.83. Found: N, 6.61; S. 7.77.

(b) 3-(1-piperidyllpropyl 4n-butylamin0-2=n- ;propomythiolb'enzoate When the procedure described above for Example 2b is followed but using S-(I-piperidyl) propyl 4-amino-2-n-propoxythiolbenzoate in place of 3 diethylaminopropyl 4 -amino 2- methoxythiolbenzoate, there is obtained 3-(1- piperidyllpropyl 4-n-butylamino-2-n-propoxythiolbenzoate.

This preparation was carried out according to the procedure described above for Example 1b but using 18.5 g. of powdered iron, 1 ml. of concentrated hydrochloric'acid, 400 ml. of dilute ethanol and 21.0 g. of 3-(1-piperidyD-propyl 4- nitro-Z-n-butoxythiolbenzoate. There was thus obtained a quantitative yield of 3-(1-piperidyl) propyl 4-amino-2-n-butoxythiolbenzoate, which in the form of its monohydrochloride salt, melted at 155.0-157.0 C. (cor.).

AnaZ.-Calcd. for C19H30N2O2S-HC1! C, 58.97;

H, 8.07; CI, 9.16. Found: C, 58.84, H, 3.10; Cl, 9.35. (b) 3-(1-piperidyDpv-opyl 4-n-butylamz'no-2-n butoxythz'oibenzoate When the procedure described above for Example 2b is followed but using 3-( 1-piperidy1) propyl 4amino-2-n-butoxythiolbenzoate in place of 3-diethylaminopropyl 4-amino-2-methoxythiolbenzoate, there is obtained 3-(1-piperidyD- propyl 4-n-butylamino-2-n-butoxythiolbenzoate.

EXAMPLE 14 (a) Z-diethylamz'noethyl 4-amino-2-n-hex0mythiolbenzoate This preparation was carried out according to the procedure described above for Example 11) but using 12.8 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 400 ml. of dilute ethanol and 16.0 g. of Z-diethylaminoethyl 4- nitro 2 n hexoxythiolbenzoate hydrochloride. There was thus obtained a quantitative yield of 2 diethylaminoethyl 4-amino'-2-n-hexoxythiolbenzoate, which in the form of its monohydrochloride salt melted at 110.2-1l1.6 C. (cor.).

AnaZ.Calcd. for C19H32N2O2S-HC11 N, 7.20; CI, 9.11. Found: N, 7.02; CI, 9.28.

(b) Z-diethylamz'noethyl 4-n-propyZdmino-2-nhexomythiolbenzoate 'Following the procedure described above for Example 2b but using Z-diethylaminoethyl 4- amino-2-n-hexoxythiolbenzoate and propionaldehyde (l-propanal) in place of 3-diethylaminopropyl 4-amino-2-methoxythiolbenzoate and nbutyraldehyde, respectively, there is obtained 2- diethylaminoethyl 4-n-propylamino-2-n-hexoxythiolbenzoate.

EXAMPLE 15 (a) Z-d 'ethylaminoethyl 4-amino-2-z'sobut0asythiolbenzoate amino) 2 isobutoxythiolbenzoate; and 2 aminopropyl 4 amino-2-methoxythiolbenzoate, there is obtained 2-diethylaminoethyl 4-n-butyl. amino-2-isobutoxythiolbenzoate.

EXAMPLE 16 2 diethylamz'noethyl 4-(5-hydroxyamylamino) Z-methomythiolbenzoate This preparation was carried out according to the procedure described above for Example 1c but using 13.0 g. of 2-diethylaminoethyl 4- amino- -methoxythiolbenzoate, 4.1 g. of zinc dust, 111g. of glacial acetic acid, 200 ml. of dry benzene and 5.70 g. of 5-hydroxy-1-pentanal' in 25 ml. of dry benzene. There was thus obtained 2-diethylaminoethyl 4- (5-hydroxyamylamino) 2-methoxythiolbenzoate, which, in the form of its dihydrochloride addition salt, melts at 140.0- 141.0 C. (cor.).

AnaZ.-Calcd. for C19Ha2N2OaS-2HCI: Cl, 16.08; S, 7.25. Found: Cl, 16.19; S, 7.29.

Other tertiary aminoalkyl 4 (hydroxyalkylamino) -2-alkoxythiolbenzoates which can be prepared according to the foregoing procedure using the appropriate tertiary-aminoalkyl 4- amino-2-alkoxythiolbenzoate and hydroxyalkanal in place of 2-diethylaminoethyl 4-amino-2- methoxythiolbenzoate and 5-hydroxy-l-pentanal, respectively, include the following: 2-diethylaminoethyl 4 (6 hydroxyhexylamino) -2- ethoxythiolbenzoate; 3-(l-pyrrolidyl)propyl 4- (5-hydroxyamylamino) 2 n-propoxythiolbenzoate; 2- (2,5-dimethyl-l-pyrrolidyl) -ethyl 4- (3-v hydroxypropyl) -2-n-hexoxythiolbenzoate 2- (3- ethyl-l-piperidyl) ethyl 4-(3-hydroXy-1-butylmorpholinyDethyl 4-(4-hydroxybutylamino) 2- n-amoxythiolbenzoate.

We claim:

1. A tertiary-aminoalkyl 4-substituted-aminoz-alkoxythiolbenzoate having the formula NHRa =" ated)-1-pyrrolidyl and 4-morpholinyl, R2 is a lower alkyl radical having from one to six carbon atoms and R3 is a member of the group consisting of lower alkyl radicals having from one to six carbon atoms and lower hydroxyalkyl radicals having from two to six carbon atoms. 2. A dialkylaminoalkyl 4-alkylamino 2 alkoxythiolbenzoate having the formula NHRs twoto four carbon atoms whose two free valence bonds are on difierent carbon atoms, and R2 and R3 are each lower alkyl radicals having from one to six carbon atoms.

'1 '3. Atertiary aminoalkyl 4-alkylamino-2-aikoxythiolbenzoate having the formula NHB:

O R a w x-Newer alk'yl),

where X is a lower alkyl'ene radical having from two to four carbon atoms whose two free valence bonds are on different carbon atomsand R2 is a lower alkyl radical having from one to six carbon atoms.

'5. A tertiary-aminoalkvl i n butvlamino-2- alkoxvthiolbenzoate having the formula NH Calv n where X is a lower alkylene radical having from two to four carbon atoms whose two free valence bonds are on difierent carbon atoms, NRRi is a l-piperidyl radical and R2 is a lower alkyl radical having from one to six carbon atoms.

'6 ll-diethylammoethyl 4-nbutylamino-Z-npropoxythiolbenzoate.

'L 3-"(1-piperidylmropyl 4'- n h 'butylamino zmethoxythiolbenzoate.

-8. -A process for the preparation of fa tertiaryaminoalkyl 4 substituted-amino-2-alkoxythio1- benzoate having the .ior'mula where X is a lower alkylene radical having from two to four carbon atoms whose two free valence bonds are on different carbon atoms, NRRI is a member selected from the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -1-piperidyl, l-py'rrolidYl, (lower alkylated)-l-"py rrolidyl and 4 morpholinyl, is a lower alkyl radical "having from one to sixcarb'o'n atoms and R3 is 'a radical havingfirom three to six carbon atoms "selected from'the'groupconsisting of lower alkyl and lower hydroxyalkyl radicals, which comprises treating a compound having the formula with a reducingagent in the presence or a compound selected from the group consisting of an alka'n'al and a hydroxyalkanal each having from three to six carbon atoms.

9. A process for the'preparation of a dialkylaminoalkyl 4 alkylamino-iz alkoxythiolbenzoate 1 having the formula NH s where X is a lower alkylene radical having from to to four carbon atoms whose two free valence bonds are on different carbon atoms, R2 is "a lower alkyl radical'having'irom one to six carbon atoms and R3 is (a lower alkvlradical having from three to six carbon atoms, whichcomprises treating a compound of the formula COS-K- N-(IQWH alkyd);

with a reducing agent in the presence of an alkanal having three to carbon atoms.

10. A process for the preparation of a tertiaryaminoalkyl =4 -:alkylamino-2ealkoxythiolbenzoate having the formiila NHR:

where X is'alower alkylene radical having from two to four carbon atomswhose two free valence bonds are on difierent-carbon atoms, NRRi is a bpiperidyl radical, R2 isa lower alkyl radical having from oneto six carbon :atoms and R3 is a lower alkyl radical having from three-to sixcarbon' atoms, whichcomprises treating a compound of the formula .0 os-x1 1 In with a reducing agent in the presence :or an alkanal havingthree to *six carbon atoms.

11. n processior the preparation or a dialkyl- 17 aminoalkyl 4 n butylamino-2-a1koxythiolbenzoate having the formula IIIH:

C O S-X-N (lower alkyl);

with a reducing agent in the presence of n-butyraldehyde.

12. A process for the preparation of a tertiaryaminoalkyl 4 n butylamino-Z-alkoxythiolbenzoate having the formula COSXNRR1 where X is a lower alkylene radical having from two to four carbon atoms whose two free valence bonds are on different carbon atoms, NRRi is a l-piperidyl radical and R2 is a lower alkyl radical having from one to six carbon atoms, which comprises treating a compound of the formula with a reducing agent in the presence of n-butyraldehyde.

13. A process for the preparation of Z-diethyl- 18 aminoethyl 4 n butylamino-z-n-propoxythiolbenzoate which comprises treating 2-diethylaminoethyl 4 amino 2-n-propoxythiolbenzoate with a reducing agent in the presence of n-butyraldehyde.

14. A process for the preparation of 3-(1- piperidyl) propyl 4 n butylamino Z-methoxythiolbenzoate which comprises treating 3-(1 piperidyl) propyl 4 amino 2-methoxythio1benzoate with a reducing agent in the presence of n-butyraldehyde.

15. 2 diethy1aminoethyl4 n amylamino 2- methoxythiolbenzoate.

16. 3 diethy1aminopropy1 4 n-butylamino-2- methoxythiolbenzoate.

17. 4 diethylaminobutyl 4 n butylamino-2- methoxythiolbenzoate.

18. A process for the preparation of 2-diethylaminoethyl 4-n-amylamino-2-methoxythiolbenzoate which comprises treating 2-diethylaminoethyl 4-amino-2-methoxythiolbenzoate with a. reducing agent in the presence of n-valeraldehyde.

19. A process for the preparation of B-diethylaminopropyl 4 n butylamino-2-methoxythiolbenzoate which comprises treating 3-diethylaminopropyl 4 amino z-methoxythiolbenzoate with a reducing agent in the presence of n-butyraldehyde.

20. A process for the preparation of 4-diethylaminobutyl 4-n-butylamino-2-methoxythiolbenzoate which comprises treating 4-diethylaminobutyl 4-amino-2methoxythiolbenzoate with a. reducing agent in the presence of n-butyraldehyde.

RAYMOND O. CLINTON. STANLEY C. LASKOWSKI.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,342,142 Harris Feb. 22, 1944 FOREIGN PATENTS Number Country Date 349,640 Great Britain 1939 OTHER REFERENCES Clinton, J. Amer. Chem. 800., March -0, vol. 72, DD. 1331-4.

Moore, J. of American Pharm. Assoc, vol 33, July 1944, Pp. 193-204. 

1. A TERTIARY-AMINOALKYL 4-SUBSTITUTED-AMINO2-ALKOXYTHIOLBENZOATE HAVING THE FORMULA 